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Blasting long-term potentiation with a Mega Buster

Mega Man (1987) was one of the most entertaining games that I remember ever playing on Nintendo. You were Dr. Light's boy android (think Astro Boy or Pinocchio) and your mission was to defeat the multitude of robot bosses threatening to destroy the world. However, the only way to defeat them was to 1) consider how to counteract their special abilities with your own abilities and 2) memorize their attack patterns, often taking hours of learning (and frustration) before you got it right. Once successful, you would acquire that particular bosses' special ability, thus expanding your arsenal, and move on to fight another epic battle (not unlike Highlander). While reading Alvarez-Salvado and colleagues' (2014) paper on fMRI and long-term potentiation (LTP), it reminded me of this game. The vivid childhood memory was triggered by my reading of their abstract in which they wrote:

Neurons are able to express long-lasting and activity-dependent modulations of their synapses. This plastic property supports memory and conveys an extraordinary adaptive value, because it allows an individual to learn from, and respond, to changes in the environment.

Without this critical process of the brain, neither I nor Rock (the boy android) could have defeated Dr. Wily's evil robots and ultimately save the world from utter destruction. In Alvarez-Solvado and his colleagues' paper, they discuss how both cellular changes and network interactions in the brain are needed to encode a pattern of neuronal activity into long-term memory through synaptic plasticity. They go on to state that although the field of neuroscience already knows a great deal about the relationship between cellular changes and long-term memory, less is known about how regulation of network interactions effect plasticity. Thus, they were interested in looking at this mechanism a bit further using their version of a Mega Buster; a combination of high resolution functional magnetic resonance imaging (fMRI) and in vivo electrophysiology, in rats.

The team triggered LTP-induced network reorganization between the hippocampus (a seahorse shaped brain structure involved in learning and memory) and neocortical ("new brain") structures such as the prefrontal cortex (involved in executive functions such as planning and organization) and the sub cortical nucleus (involved in voluntary movement). They found that there was an enhancement of connection between these two brain regions via stimulation of the perforant pathway. The perforant pathway is a connective route between the entorhinal cortex to all fields of the hippocampus (think about the entorhinal cortex as the major highway between the hippocampus and the neocortex and the perforant pathway as the exit off the entorhinal cortex highway leading to the hippocampus). The perforant pathway plays a significant role in spatial memory and learning.

Image of perforant pathway from Learning and Memory (2009).16: 504-507

More specifically, Alvarez-Solvado et al. observed, through their high-res imaging, a fast increase in communication between the hippocampus and the prefrontal cortex mediated by N-methyl-D-aspartate (NMDA) receptors, the predominant molecular device for controlling synaptic plasticity and memory. From this finding they suggest that there may be two memory buffers functioning in parallel during memory encoding. They also observed that when LTP-induction was triggered on one side of the hippocampus, there was functional activation on the other side of hippocampus as well, supported by white matter structures that connect hemispheres of the brain. They believe this finding may represent bilateral coordination of associational networks with a role in pattern separation and sequence learning, all critical skills to have if you want to beat a game like Mega Man (and accomplish more important things, of course).